bims-mitmed 2023-03-05 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023‒03‒05
thirty-one papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

Variants in ATP5F1B are associated with dominantly inherited dystonia.
Editorial: Mitochondrial therapy in neurodegeneration.
Dysfunctional mitochondria accumulate in a skeletal muscle knockout model of Smn1, the causal gene of spinal muscular atrophy.
Rescuers from the Other Shore: Intercellular Mitochondrial Transfer and Its Implications in Central Nervous System Injury and Diseases.
Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.
Mitochondrial Transport in Axons with Multiple Branching Junctions: A Computational Study.
The multifaceted roles of natural products in mitochondrial dysfunction.
Evaluating mitochondrial length, volume, and cristae ultrastructure in rare mouse adult stem cell populations.
Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties.
Defective COX1 expression in aging mice liver.
The multifaceted mitochondrial OXA insertase.
Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing.
Targeting the liver to treat the eye.
Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice.
Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.
A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.
Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using Seahorse technology.
Expanding the Spectrum of NUBPL-Related Leukodystrophy.
Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.
A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling.
mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs.
TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway.
Mitochondrial ROS production, oxidative stress and aging within and between species: Evidences and recent advances on this aging effector.
Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative.
Italian cross-cultural adaptation of the patient-reported outcome measure of ataxia.
Analysis of mitochondrial double-stranded RNAs in human cells.
Goliath induces inflammation in obese mice by linking fatty acid β-oxidation to glycolysis.
Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.
Transplantation of Human Placenta Derived Mitochondria Promotes Cell Communication in Endometrium in a Murine Model of Disturbed Endometrium.
Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.

Brain. 2023 Mar 01. pii: awad068. [Epub ahead of print]

Variants in ATP5F1B are associated with dominantly inherited dystonia.

Alessia Nasca, Niccolò E Mencacci, Federica Invernizzi, Michael Zech, Ignacio J Keller Sarmiento, Andrea Legati, Chiara Frascarelli, Bernabe I Bustos, Luigi M Romito, Dimitri Krainc, Juliane Winkelmann, Miryam Carecchio, Nardo Nardocci, Giovanna Zorzi, Holger Prokisch, Steven J Lubbe, Barbara Garavaglia, Daniele Ghezzi.

  ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

Keywords:  ATP5F1B; case report; dystonia; incomplete penetrance; mitochondrial ATP synthase

DOI:  https://doi.org/10.1093/brain/awad068
Front Pharmacol. 2023 ;14 1144093

Editorial: Mitochondrial therapy in neurodegeneration.

Anuradha Kalani, Pankaj Chaturvedi, Dario Brunetti, Komal Kalani.



Keywords:  Alzheimer’s; Parkinson’s; mitochondria; neurodegeneration; therapy

DOI:  https://doi.org/10.3389/fphar.2023.1144093
Cell Death Dis. 2023 Feb 27. 14(2): 162

Dysfunctional mitochondria accumulate in a skeletal muscle knockout model of Smn1, the causal gene of spinal muscular atrophy.

Francesco Chemello, Michela Pozzobon, Lorenza Iolanda Tsansizi, Tatiana Varanita, Rubèn Quintana-Cabrera, Daniele Bonesso, Martina Piccoli, Gerolamo Lanfranchi, Marta Giacomello, Luca Scorrano, Camilla Bean.

The approved gene therapies for spinal muscular atrophy (SMA), caused by loss of survival motor neuron 1 (SMN1), greatly ameliorate SMA natural history but are not curative. These therapies primarily target motor neurons, but SMN1 loss has detrimental effects beyond motor neurons and especially in muscle. Here we show that SMN loss in mouse skeletal muscle leads to accumulation of dysfunctional mitochondria. Expression profiling of single myofibers from a muscle specific Smn1 knockout mouse model revealed down-regulation of mitochondrial and lysosomal genes. Albeit levels of proteins that mark mitochondria for mitophagy were increased, morphologically deranged mitochondria with impaired complex I and IV activity and respiration and that produced excess reactive oxygen species accumulated in Smn1 knockout muscles, because of the lysosomal dysfunction highlighted by the transcriptional profiling. Amniotic fluid stem cells transplantation that corrects the SMN knockout mouse myopathic phenotype restored mitochondrial morphology and expression of mitochondrial genes. Thus, targeting muscle mitochondrial dysfunction in SMA may complement the current gene therapy.

DOI: https://doi.org/10.1038/s41419-023-05573-x
Cell Mol Neurobiol. 2023 Mar 03.

Rescuers from the Other Shore: Intercellular Mitochondrial Transfer and Its Implications in Central Nervous System Injury and Diseases.

Weichen Dong, Wenxin Zhang, Linying Yuan, Yi Xie, Yunzi Li, Kuanyu Li, Wusheng Zhu.

  As the powerhouse and core of cellular metabolism and survival, mitochondria are the essential organelle in mammalian cells and maintain cellular homeostasis by changing their content and morphology to meet demands through mitochondrial quality control. It has been observed that mitochondria can move between cells under physiological and pathophysiological conditions, which provides a novel strategy for preserving mitochondrial homeostasis and also a therapeutic target for applications in clinical settings. Therefore, in this review, we will summarize currently known mechanisms of intercellular mitochondrial transfer, including modes, triggers, and functions. Due to the highly demanded energy and indispensable intercellular linkages of the central nervous system (CNS), we highlight the mitochondrial transfer in CNS. We also discuss future application possibilities and difficulties that need to be addressed in the treatment of CNS injury and diseases. This clarification should shed light on its potential clinical applications as a promising therapeutic target in neurological diseases. Intercellular mitochondrial transfer maintains the homeostasis of central nervous system (CNS), and its alteration is related to several neurological diseases. Supplementing exogenous mitochondrial donor cells and mitochondria, or utilizing some medications to regulate the process of transfer might mitigate the disease and injury.

Keywords:  Central nervous system; Intercellular mitochondrial transfer; Mitochondria; Mitochondrial quality control; Mitochondrial transplantation

DOI:  https://doi.org/10.1007/s10571-023-01331-x
Mol Cell Neurosci. 2023 Mar 01. pii: S1044-7431(23)00028-3. [Epub ahead of print] 103834

Compartment specific mitochondrial dysfunction in Drosophila knock-in model of ALS reversed by altered gene expression of OXPHOS subunits and pro-fission factor Drp1.

Y Nemtsova, B L Steinert, K A Wharton.

  Amyotrophic Lateral Sclerosis (ALS) is a fatal multisystem neurodegenerative disease, characterized by a loss in motor function. ALS is genetically diverse, with mutations in genes ranging from those regulating RNA metabolism, like TAR DNA-binding protein (TDP-43) and Fused in sarcoma (FUS), to those that act to maintain cellular redox homeostasis, like superoxide dismutase 1 (SOD1). Although varied in genetic origin, pathogenic and clinical commonalities are clearly evident between cases of ALS. Defects in mitochondria is one such common pathology, thought to occur prior to, rather than as a consequence of symptom onset, making these organelles a promising therapeutic target for ALS, as well as other neurodegenerative diseases. Depending on the homeostatic needs of neurons throughout life, mitochondria are normally shuttled to different subcellular compartments to regulate metabolite and energy production, lipid metabolism, and buffer calcium. While originally considered a motor neuron disease due to the dramatic loss in motor function accompanied by motor neuron cell death in ALS patients, many studies have now implicated non-motor neurons and glial cells alike. Defects in non-motor neuron cell types often preceed motor neuron death suggesting their dysfunction may initiate and/or facilitate the decline in motor neuron health. Here, we investigate mitochondria in a Drosophila Sod1 knock-in model of ALS. In depth, in vivo, examination reveals mitochondrial dysfunction evident prior to onset of motor neuron degeneration. Genetically encoded redox biosensors identify a general disruption in the electron transport chain (ETC). Compartment specific abnormalities in mitochondrial morphology is observed in diseased sensory neurons, accompanied by no apparent defects in the axonal transport machinery, but instead an increase in mitophagy in synaptic regions. The decrease in networked mitochondria at the synapse is reversed upon downregulation of the pro-fission factor Drp1. Furthermore, altered expression of specific OXPHOS subunits reverses ALS-associated defects in mitochondrial morphology and function.

Keywords:  ALS; Drosophila; Mitochondrial dysfunction; Neurodegeneration; Sensory neurons

DOI:  https://doi.org/10.1016/j.mcn.2023.103834
bioRxiv. 2023 Feb 23. pii: 2023.02.22.529604. [Epub ahead of print]

Mitochondrial Transport in Axons with Multiple Branching Junctions: A Computational Study.

Ivan A Kuznetsov, Andrey V Kuznetsov.

We explore the impact of multiple branching junctions in axons on the mean age of mitochondria and their age density distributions in demand sites. The study looked at mitochondrial concentration, mean age, and age density distribution in relation to the distance from the soma. We developed models for a symmetric axon containing 14 demand sites and an asymmetric axon containing 10 demand sites. We examined how the concentration of mitochondria changes when an axon is divided into two branches at the branching junction. We also studied whether mitochondria concentrations in the branches are affected by what portion of mitochondrial flux goes into the upper branch and what portion goes into the lower branch. Additionally, we explored whether the distributions of mitochondria mean age and age density in branching axons are affected by how the mitochondria flux splits at the branching junction. Our findings elucidate the effects of axonal branching on mitochondria age. Mitochondria aging is the focus of this study as recent research suggests it may be involved in neurodegenerative disorders.

DOI: https://doi.org/10.1101/2023.02.22.529604
Front Pharmacol. 2023 ;14 1093038

The multifaceted roles of natural products in mitochondrial dysfunction.

Qianrun Chen, Danhua Ruan, Jiayan Shi, Dongru Du, Ce Bian.

  Mitochondria are the primary source of energy production in cells, supporting the metabolic demand of tissue. The dysfunctional mitochondria are implicated in various diseases ranging from neurodegeneration to cancer. Therefore, regulating dysfunctional mitochondria offers a new therapeutic opportunity for diseases with mitochondrial dysfunction. Natural products are pleiotropic and readily obtainable sources of therapeutic agents, which have broad prospects in new drug discovery. Recently, many mitochondria-targeting natural products have been extensively studied and have shown promising pharmacological activity in regulating mitochondrial dysfunction. Hence, we summarize recent advances in natural products in targeting mitochondria and regulating mitochondrial dysfunction in this review. We discuss natural products in terms of their mechanisms on mitochondrial dysfunction, including modulating mitochondrial quality control system and regulating mitochondrial functions. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products, emphasizing the potential value of natural products in mitochondrial dysfunction.

Keywords:  drug repurposing; mitochondria; mitochondrial dysfunction; nanotechnology; natural products

DOI:  https://doi.org/10.3389/fphar.2023.1093038
STAR Protoc. 2023 Feb 09. pii: S2666-1667(23)00065-5. [Epub ahead of print]4(1): 102107

Evaluating mitochondrial length, volume, and cristae ultrastructure in rare mouse adult stem cell populations.

Matthew Triolo, Steven Wade, Nicole Baker, Mireille Khacho.

  Since changes in mitochondrial morphology regulate key functions of stem cells, it is important to assess their structure under physiological and pathophysiological conditions. Here, we present techniques optimized in rare adult muscle stem cells (MuSCs). For evaluating mitochondrial length and volume within a compact cytoplasmic area in MuSCs on intact myofibers, we describe steps for mitochondrial staining, imaging, and quantification. For evaluating mitochondrial ultrastructure in small cell numbers, we describe steps for agarose embedding and quantification by TEM. For complete details on generation and use of this protocol, please refer to Baker et al. (2022).1.

Keywords:  Cell Biology; Metabolism; Microscopy; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2023.102107
Brain Commun. 2023 ;5(1): fcad007

Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties.

Chiara Dionisi, Marine Chazalon, Myriam Rai, Céline Keime, Virginie Imbault, David Communi, Hélène Puccio, Serge N Schiffmann, Massimo Pandolfo.

  Friedreich ataxia is an autosomal recessive multisystem disorder with prominent neurological manifestations and cardiac involvement. The disease is caused by large GAA expansions in the first intron of the FXN gene, encoding the mitochondrial protein frataxin, resulting in downregulation of gene expression and reduced synthesis of frataxin. The selective loss of proprioceptive neurons is a hallmark of Friedreich ataxia, but the cause of the specific vulnerability of these cells is still unknown. We herein perform an in vitro characterization of human induced pluripotent stem cell-derived sensory neuronal cultures highly enriched for primary proprioceptive neurons. We employ neurons differentiated from healthy donors, Friedreich ataxia patients and Friedreich ataxia sibling isogenic control lines. The analysis of the transcriptomic and proteomic profile suggests an impairment of cytoskeleton organization at the growth cone, neurite extension and, at later stages of maturation, synaptic plasticity. Alterations in the spiking profile of tonic neurons are also observed at the electrophysiological analysis of mature neurons. Despite the reversal of the repressive epigenetic state at the FXN locus and the restoration of FXN expression, isogenic control neurons retain many features of Friedreich ataxia neurons. Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals. It also highlights the need for further investigations to better understand the mechanistic link between FXN silencing and proprioceptive degeneration in Friedreich ataxia.

Keywords:  Friedreich ataxia; in vitro characterization; induced-pluripotent stem cells; isogenic controls; proprioceptive neurons

DOI:  https://doi.org/10.1093/braincomms/fcad007
Biol Open. 2023 Mar 15. pii: bio059844. [Epub ahead of print]12(3):

Defective COX1 expression in aging mice liver.

Steffen Witte, Angela Boshnakovska, Metin Özdemir, Arpita Chowdhury, Peter Rehling, Abhishek Aich.

  Mitochondrial defects are associated with aging processes and age-related diseases, including cardiovascular diseases, neurodegenerative diseases and cancer. In addition, some recent studies suggest mild mitochondrial dysfunctions appear to be associated with longer lifespans. In this context, liver tissue is considered to be largely resilient to aging and mitochondrial dysfunction. Yet, in recent years studies report dysregulation of mitochondrial function and nutrient sensing pathways in ageing livers. Therefore, we analyzed the effects of the aging process on mitochondrial gene expression in liver using wildtype C57BL/6N mice. In our analyses, we observed alteration in mitochondrial energy metabolism with age. To assess if defects in mitochondrial gene expression are linked to this decline, we applied a Nanopore sequencing based approach for mitochondrial transcriptomics. Our analyses show that a decrease of the Cox1 transcript correlates with reduced respiratory complex IV activity in older mice livers.

Keywords:  Ageing; Mitochondria; Nanopore; Transcriptomics

DOI:  https://doi.org/10.1242/bio.059844
Trends Cell Biol. 2023 Feb 28. pii: S0962-8924(23)00020-X. [Epub ahead of print]

The multifaceted mitochondrial OXA insertase.

Bettina Homberg, Peter Rehling, Luis Daniel Cruz-Zaragoza.

  Most mitochondrial proteins are synthesized in the cytosol and transported into mitochondria by protein translocases. Yet, mitochondria contain their own genome and gene expression system, which generates proteins that are inserted in the inner membrane by the oxidase assembly (OXA) insertase. OXA contributes to targeting proteins from both genetic origins. Recent data provides insights into how OXA cooperates with the mitochondrial ribosome during synthesis of mitochondrial-encoded proteins. A picture of OXA emerges in which it coordinates insertion of OXPHOS core subunits and their assembly into protein complexes but also participates in the biogenesis of select imported proteins. These functions position the OXA as a multifunctional protein insertase that facilitates protein transport, assembly, and stability at the inner membrane.

Keywords:  mitochondria; oxidase assembly; oxidative phosphorylation; protein translocation; ribosomes

DOI:  https://doi.org/10.1016/j.tcb.2023.02.001
Sci Adv. 2023 Mar;9(9): eadd5220

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.

Francesco Petrelli, Valentina Scandella, Sylvie Montessuit, Nicola Zamboni, Jean-Claude Martinou, Marlen Knobloch.

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

DOI: https://doi.org/10.1126/sciadv.add5220
J Vis Exp. 2023 Feb 10.

Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing.

Pavel A Nash, Pedro Silva-Pinheiro, Michal A Minczuk.

Mutations in the mitochondrial genome (mtDNA) have been associated with maternally inherited genetic diseases. However, interest in mtDNA polymorphisms has increased in recent years due to the recently developed ability to produce models by mtDNA mutagenesis and a new appreciation of the association between mitochondrial genetic aberrations and common age-related diseases such as cancer, diabetes, and dementia. Pyrosequencing is a sequencing-by-synthesis technique that is widely employed across the mitochondrial field for routine genotyping experiments. Its relative affordability when compared to massive parallel sequencing methods and ease of implementation make it an invaluable technique in the field of mitochondrial genetics, allowing for the rapid quantification of heteroplasmy with increased flexibility. Despite the practicality of this method, its implementation as a means of mtDNA genotyping requires the observation of certain guidelines, specifically to avoid certain biases of biological or technical origin. This protocol outlines the necessary steps and precautions in designing and implementing pyrosequencing assays for use in the context of heteroplasmy measurement.

DOI: https://doi.org/10.3791/64361
EMBO Mol Med. 2023 Feb 27. e17285

Targeting the liver to treat the eye.

Berna Seker Yilmaz, Paul Gissen.

Over the last two decades, gene therapy has given hope of potential cure for many rare diseases. In the simplest form, gene therapy is the transfer or editing of a genetic material to cure a disease via nonviral or viral vehicles. Gene therapy can be performed either in vivo by injecting a vector carrying the gene or tools for gene editing directly into a tissue or into the systemic circulation, or ex vivo when patient cells are genetically modified outside of the body and then introduced back into the patient (Yilmaz et al, 2022). Adeno-associated viral vectors (AAV) have been the vectors of choice for in vivo gene therapy. There has been a lot of promising research on the development of novel tissue and cell-specific serotypes in order to improve efficacy and safety for clinical applications (Kuzmin et al, 2021). In this issue of EMBO Molecular Medicine, Boffa and colleagues present a novel AAV-based liver-directed gene therapy for ornithine aminotransferase deficiency.

DOI: https://doi.org/10.15252/emmm.202217285
Nat Commun. 2023 Mar 01. 14(1): 1172

Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice.

Blanca Jiménez-Gómez, Patricia Ortega-Sáenz, Lin Gao, Patricia González-Rodríguez, Paula García-Flores, Navdeep Chandel, José López-Barneo.

The hypoxic ventilatory response (HVR) is a life-saving reflex, triggered by the activation of chemoreceptor glomus cells in the carotid body (CB) connected with the brainstem respiratory center. The molecular mechanisms underlying glomus cell acute oxygen (O2) sensing are unclear. Genetic disruption of mitochondrial complex I (MCI) selectively abolishes the HVR and glomus cell responsiveness to hypoxia. However, it is unknown what functions of MCI (metabolic, proton transport, or signaling) are essential for O2 sensing. Here we show that transgenic mitochondrial expression of NDI1, a single-molecule yeast NADH/quinone oxidoreductase that does not directly contribute to proton pumping, fully recovers the HVR and glomus cell sensitivity to hypoxia in MCI-deficient mice. Therefore, maintenance of mitochondrial NADH dehydrogenase activity and the electron transport chain are absolutely necessary for O2-dependent regulation of breathing. NDI1 expression also rescues other systemic defects caused by MCI deficiency. These data explain the role of MCI in acute O2 sensing by arterial chemoreceptors and demonstrate the optimal recovery of complex organismal functions by gene therapy.

DOI: https://doi.org/10.1038/s41467-023-36894-2
J Neurol. 2023 Mar 01.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.

Rebecca Kerestes, Hannah Cummins, Nellie Georgiou-Karistianis, Louisa P Selvadurai, Louise A Corben, Martin B Delatycki, Gary F Egan, Ian H Harding.

  Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

Keywords:  Anterior; Cerebellum; Dentate; Friedreich ataxia; Resting state; Superior

DOI:  https://doi.org/10.1007/s00415-023-11637-x
Parkinsonism Relat Disord. 2023 Feb 27. pii: S1353-8020(23)00076-7. [Epub ahead of print]109 105353

A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.

Huan-Yun Chen, Han-I Lin, Chia-Lang Hsu, Pei-Lung Chen, Cheng-Yen Huang, Shu-Chun Teng, Chin-Hsien Lin.

BACKGROUND: Mitochondrial membrane protein‒associated neurodegeneration (MPAN) is a rare genetic disease characterized by progressive neurodegeneration with brain iron accumulations combined with neuronal α-synuclein and tau aggregations. Mutations in C19orf12 have been associated with both autosomal recessive and autosomal dominant inheritance patterns of MPAN.METHODS: We present clinical features and functional evidence from a Taiwanese family with autosomal dominant MPAN caused by a novel heterozygous frameshift and nonsense mutation in C19orf12, c273_274 insA (p.P92Tfs*9). To verify the pathogenicity of the identified variant, we examined the mitochondrial function, morphology, protein aggregation, neuronal apoptosis, and RNA interactome in p.P92Tfs*9 mutant knock-in SH-SY5Y cells created with CRISPR-Cas9 technology.
RESULTS: Clinically, the patients with the C19orf12 p.P92Tfs*9 mutation presented with generalized dystonia, retrocollis, cerebellar ataxia, and cognitive decline, starting in their mid-20s. The identified novel frameshift mutation is located in the evolutionarily conserved region of the last exon of C19orf12. In vitro studies revealed that the p.P92Tfs*9 variant is associated with impaired mitochondrial function, reduced ATP production, aberrant mitochondria interconnectivity and ultrastructure. Increased neuronal α-synuclein and tau aggregations, and apoptosis were observed under conditions of mitochondrial stress. Transcriptomic analysis revealed that the expression of genes in clusters related to mitochondrial fission, lipid metabolism, and iron homeostasis pathways was altered in the C19orf12 p.P92Tfs*9 mutant cells compared to control cells.
CONCLUSION: Our findings provide clinical, genetic, and mechanistic insight revealing a novel heterozygous C19orf12 frameshift mutation to be a cause of autosomal dominant MPAN, further strengthening the importance of mitochondrial dysfunction in the pathogenesis of MPAN.

DOI: https://doi.org/10.1016/j.parkreldis.2023.105353
STAR Protoc. 2023 Jan 28. pii: S2666-1667(23)00031-X. [Epub ahead of print]4(1): 102073

Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using Seahorse technology.

Yanxin Fan, Yoko Mizoguchi, Megumi Tatematsu, Monika I Linder, Stephanie Frenz, Jongsu Choi, Christoph Klein.

  Mitochondrial metabolism is critical in hematopoietic stem cell maintenance and differentiation. Here, we present a step-by-step protocol to efficiently differentiate human induced pluripotent stem cells into myeloid progenitors by a robust feeder- and serum-free system. Furthermore, we provide a protocol to subsequently assess mitochondrial function in iPSC-derived myeloid progenitors. We comprehensively describe a protocol to analyze and to quantify key parameters of mitochondrial respiration of iPSC-derived myeloid progenitors by the Seahorse XFe96 Analyzer. Additionally, our protocol includes extensive troubleshooting suggestions. For complete details on the use and execution of this protocol, please refer to Fan et al. (2022).1.

Keywords:  Cell Biology; Cell Differentiation; Immunology; Metabolism; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2023.102073
Neuropediatrics. 2023 Mar 03.

Expanding the Spectrum of NUBPL-Related Leukodystrophy.

Davide Tonduti, Alberto A Zambon, Daniele Ghezzi, Eleonora Lamantea, Rossella Izzo, Cecilia Parazzini, Cristina Baldoli, Marjo S van der Knaap, Francesca Fumagalli.

Mitochondrial leukodystrophies constitute a group of different conditions presenting with a wide range of clinical presentation but with some shared neuroradiological features. Genetic defects in NUBPL have been recognized as cause of a pediatric onset mitochondrial leukodystrophy characterized by onset at the end of the first year of life with motor delay or regression and cerebellar signs, followed by progressive spasticity. Early magnetic resonance imagings (MRIs) show white matter abnormalities with predominant involvement of frontoparietal regions and corpus callosum. A striking cerebellar involvement is usually observed. Later MRIs show spontaneous improvement of white matter abnormalities but worsening of the cerebellar involvement evolving to global atrophy and progressive involvement of brainstem. After the 7 cases initially described, 11 more subjects were reported. Some of them were similar to patients from the original series while few others broadened the phenotypic spectrum. We performed a literature review and report on a new patient who further expand the spectrum of NUBPL-related leukodystrophy. With our study we confirm that the association of cerebral white matter and cerebellar cortex abnormalities is a feature commonly observed in early stages of the disease but beside the original and so far prevalent presentation, there are also uncommon phenotypes: clinical onset can be earlier and more severe than previously thought and signs of extraneurological involvement can be observed. Brain white matter can be diffusely abnormal without anteroposterior gradient, can progressively worsen, and cystic degeneration can be present. Thalami can be involved. Basal ganglia can also become involved during disease evolution.

DOI: https://doi.org/10.1055/s-0043-1764214
Neurochem Res. 2023 Mar 01.

Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.

Gajendra Singh, Alok Kumar.

  Mitochondria dysfunction may be an important contributor to Japanese encephalitis (JE) viral infection disease pathogenesis. In the current study, we define whether changes in mitochondrial DNA copy number (which is the biomarker for mitochondrial function) and alteration in mitochondria dynamics (fusion and fission) contribute to the pathology of the JE virus in vivo mice model. We found decreased mitochondria copy number, reduced activation of mitochondrial fission (FIS1/DRP1), and increased activation of mitochondrial fusion (MFN1/MFN2/OPA1) genes that are associated with increased NOX2-mediated ROS generation and neuronal cell death following JE virus infection. Furthermore, we found that antioxidant glutathione level decreases. In summary, the following study demonstrates that JE viral infection causes an imbalance in mitochondrial fission/fusion gene activation and promotes NOX2-mediated oxidative stress and cell death, suggesting that intervention in mitochondrial dynamics might be a potential therapeutic strategy for combating oxidative stress and inflammatory process in JE viral infection.

Keywords:  JE viral infection; Mitochondria copy number; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion

DOI:  https://doi.org/10.1007/s11064-023-03898-9
EMBO J. 2023 Feb 27. e111148

A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling.

Lingxin Zhu, Yi Tang, Xiao-Yan Li, Samuel A Kerk, Costas A Lyssiotis, Wenqing Feng, Xiaoyue Sun, Geoffrey E Hespe, Zijun Wang, Marc P Stemmler, Simone Brabletz, Thomas Brabletz, Evan T Keller, Jun Ma, Jung-Sun Cho, Jingwen Yang, Stephen J Weiss.

  Osteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.

Keywords:  Zeb1; bone resorption; mitochondrial creatine kinase; osteoclast; skeletal remodeling

DOI:  https://doi.org/10.15252/embj.2022111148
Nat Commun. 2023 Feb 27. 14(1): 1121

mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs.

Zhenzhen Chen, Qiankun He, Tiankun Lu, Jiayi Wu, Gaoli Shi, Luyun He, Hong Zong, Benyu Liu, Pingping Zhu.

Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal.

DOI: https://doi.org/10.1038/s41467-023-36651-5
J Immunother Cancer. 2023 Mar;pii: e005430. [Epub ahead of print]11(3):

TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway.

Tianqi Lu, Ziqi Zhang, Zhenfei Bi, Tianxia Lan, Hao Zeng, Yu Liu, Fei Mo, Jingyun Yang, Siyuan Chen, Xuemei He, Weiqi Hong, Zhe Zhang, Ruyu Pi, Wenyan Ren, Xiaohe Tian, Yuquan Wei, Min Luo, Xiawei Wei.

BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors.METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs.
RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models.
CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future.

DOI: https://doi.org/10.1136/jitc-2022-005430
Exp Gerontol. 2023 Feb 27. pii: S0531-5565(23)00055-4. [Epub ahead of print]174 112134

Mitochondrial ROS production, oxidative stress and aging within and between species: Evidences and recent advances on this aging effector.

José Gómez, Natàlia Mota-Martorell, Mariona Jové, Reinald Pamplona, Gustavo Barja.

  Mitochondria play a wide diversity of roles in cell physiology and have a key functional implication in cell bioenergetics and biology of free radicals. As the main cellular source of oxygen radicals, mitochondria have been postulated as the mediators of the cellular decline associated with the biological aging. Recent evidences have shown that mitochondrial free radical production is a highly regulated mechanism contributing to the biological determination of longevity which is species-specific. This mitochondrial free radical generation rate induces a diversity of adaptive responses and derived molecular damage to cell components, highlighting mitochondrial DNA damage, with biological consequences that influence the rate of aging of a given animal species. In this review, we explore the idea that mitochondria play a fundamental role in the determination of animal longevity. Once the basic mechanisms are discerned, molecular approaches to counter aging may be designed and developed to prevent or reverse functional decline, and to modify longevity.

Keywords:  Aging rate; Animal longevity; Complex I; DNA damage; DNA fragments; Electron transport chain; FeS N1a iron-sulfur cluster; NDUFV2 subunit

DOI:  https://doi.org/10.1016/j.exger.2023.112134
Cerebellum. 2023 Mar 04.

Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative.

AGI Ataxia NGS genomics, platforms Working Group

  The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% of patients with hereditary ataxia remain genetically undiagnosed. One current shortcoming is the fragmentation of patients and NGS datasets on different analysis platforms and databases around the world. The AGI NGS working group in collaboration with the AGI associated research platforms-CAGC, GENESIS, and RD-Connect GPAP-provides clinicians and scientists access to user-friendly and adaptable interfaces to analyze genome-scale patient data. These platforms also foster collaboration within the ataxia community. These efforts and tools have led to the diagnosis of > 500 ataxia patients and the discovery of > 30 novel ataxia genes. Here, the AGI NGS working group presents their consensus recommendations for NGS data sharing initiatives in the ataxia field, focusing on harmonized NGS variant analysis and standardized clinical and metadata collection, combined with collaborative data and analysis tool sharing across platforms.

Keywords:  Cerebellar ataxia; Consensus; Genomics; High-throughput nucleotide sequencing; Information dissemination

DOI:  https://doi.org/10.1007/s12311-023-01537-1
Neurol Sci. 2023 Mar 04.

Italian cross-cultural adaptation of the patient-reported outcome measure of ataxia.

Anna Castaldo, Mariangela Farinotti, Mario Fichera, Lorenzo Nanetti, Filippo Fortuna, Caterina Mariotti, Alessandra Solari.

  BACKGROUND: The patient-reported outcome measure of ataxia (PROM-Ataxia) is the first patient-reported questionnaire specifically developed for use in patients with cerebellar ataxia. The scale was recently designed and validated in English language, and it consists of 70 items encompassing all aspects associated with the patient experience, including physical and mental health and their consequences on activities of daily living. The aim of the study was to translate and culturally adapt into Italian the PROM-Ataxia questionnaire, before assessing its psychometric properties.METHODS: We translated and culturally adapted into Italian the PROM-Ataxia following the ISPOR TCA Task Force guidelines. The questionnaire was field tested via cognitive interviews with users.
RESULTS: The Italian patients found that the questionnaire was complete, and no significant contents related to the physical, mental, and functional dimensions were missing. Some items were found redundant or ambiguous. Most of the identified issues pertained to semantic equivalence, and a few to conceptual and normative equivalence, while the questionnaire did not contain any idiomatic expression.
CONCLUSIONS: The translation and cultural adaptation of the PROM-Ataxia questionnaire in the Italian patient population represent the pre-requisite for the subsequent psychometric validation of the scale. This instrument may be valuable for cross-country comparability that would allow the merging of the data in collaborative multinational research studies.

Keywords:  Italian questionnaire; Linguistic validation; PROM-Ataxia; Scale translation

DOI:  https://doi.org/10.1007/s10072-023-06714-y
STAR Protoc. 2023 Jan 18. pii: S2666-1667(22)00887-5. [Epub ahead of print]4(1): 102007

Analysis of mitochondrial double-stranded RNAs in human cells.

Sujin Kim, Jimin Yoon, Keonyong Lee, Yoosik Kim.

  Human mitochondrial genome is transcribed bidirectionally, generating long complementary RNAs that can form double-stranded RNAs (mt-dsRNAs). When released to the cytosol, these mt-dsRNAs can activate antiviral signaling. Here, we present a detailed protocol for the analysis of mt-dsRNA expression. The protocol provides three approaches that can complement one another in examining mt-dsRNAs. While the described protocol is optimized for human cells, this approach can be adapted for use in other animal cell lines and tissue samples. For complete details on the use and execution of this protocol, please refer to Kim et al. (2022).1.

Keywords:  Biotechnology and bioengineering; Cell biology; Immunology; Molecular biology; Protein biochemistry; Protein expression and purification

DOI:  https://doi.org/10.1016/j.xpro.2022.102007
EMBO Rep. 2023 Mar 02. e56932

Goliath induces inflammation in obese mice by linking fatty acid β-oxidation to glycolysis.

Shumeng Hao, Sulin Zhang, Jialin Ye, Lifan Chen, Yan Wang, Siyu Pei, Qingchen Zhu, Jing Xu, Yongzhen Tao, Neng Zhou, Huiyong Yin, Cai-Wen Duan, Chaoming Mao, Mingyue Zheng, Yichuan Xiao.

  Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity-associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4+ T cells from obese mice exhibit elevated basal levels of fatty acid β-oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate-limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF-AT signaling, thereby promoting glycolysis and hyperactivation of CD4+ T cells in obesity. We also report the specific GOLIATH inhibitor DC-Gonib32, which blocks this FAO-glycolysis metabolic axis in CD4+ T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath-bridged FAO-glycolysis axis in mediating CD4+ T cell hyperactivation and thus inflammation in obese mice.

Keywords:  FAO; Goliath; glycolysis; inflammation; obesity

DOI:  https://doi.org/10.15252/embr.202356932
Orphanet J Rare Dis. 2023 Mar 02. 18(1): 43

Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.

Tsz-Sum Wong, Kiran M Belaramani, Chun-Kong Chan, Wing-Ki Chan, Wai-Lun Larry Chan, Shek-Kwan Chang, Sing-Ngai Cheung, Ka-Yin Cheung, Yuk-Fai Cheung, Shuk-Ching Josephine Chong, Chi-Kwan Jasmine Chow, Hon-Yin Brian Chung, Sin-Ying Florence Fan, Wai-Ming Joshua Fok, Ka-Wing Fong, Tsui-Hang Sharon Fung, Kwok-Fai Hui, Ting-Hin Hui, Joannie Hui, Chun-Hung Ko, Min-Chung Kwan, Mei-Kwan Anne Kwok, Sung-Shing Jeffrey Kwok, Moon-Sing Lai, Yau-On Lam, Ching-Wan Lam, Ming-Chung Lau, Chun-Yiu Eric Law, Wing-Cheong Lee, Han-Chih Hencher Lee, Chin-Nam Lee, Kin-Hang Leung, Kit-Yan Leung, Siu-Hung Li, Tsz-Ki Jacky Ling, Kam-Tim Timothy Liu, Fai-Man Lo, Hiu-Tung Lui, Ching-On Luk, Ho-Ming Luk, Che-Kwan Ma, Karen Ma, Kam-Hung Ma, Yuen-Ni Mew, Alex Mo, Sui-Fun Ng, Wing-Kit Grace Poon, Richard Rodenburg, Bun Sheng, Jan Smeitink, Cheuk-Ling Charing Szeto, Shuk-Mui Tai, Choi-Ting Alan Tse, Li-Yan Lilian Tsung, Ho-Ming June Wong, Wing-Yin Winnie Wong, Kwok-Kui Wong, Suet-Na Sheila Wong, Chun-Nei Virginia Wong, Wai-Shan Sammy Wong, Chi-Kin Felix Wong, Shun-Ping Wu, Hiu-Fung Jerome Wu, Man-Mut Yau, Kin-Cheong Eric Yau, Wai-Lan Yeung, Hon-Ming Jonas Yeung, Kin-Keung Edwin Yip, Pui-Hong Terence Young, Gao Yuan, Yuet-Ping Liz Yuen, Chi-Lap Yuen, Cheuk-Wing Fung.

  OBJECTIVE: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region.METHODS: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators.
RESULTS: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%.
CONCLUSION: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.

Keywords:  Hong Kong; Mitochondrial diseases; Prevalence

DOI:  https://doi.org/10.1186/s13023-023-02632-6
Stem Cell Rev Rep. 2023 Mar 01.

Transplantation of Human Placenta Derived Mitochondria Promotes Cell Communication in Endometrium in a Murine Model of Disturbed Endometrium.

Jeevitaa Kshersagar, Lavanya Pulgam, Mrunal N Damle, Kishore Tardalkar, Rakesh Sharma, Meghnad G Joshi.

  OBJECTIVES: Herein, we investigated the regenerative potential of functional mitochondria to restore endometrial injury.METHODS: The endometrium was disturbed with an intrauterine injection of 95% ethanol. Regeneration of the disturbed endometrium was achieved by transplantation of human placenta derived mitochondria followed by thrombin activated platelet rich plasma (hMTx). The transplantation method provided a biomimetic gel layer that stabilized and supported the functionality of the transplanted mitochondria to flourish regeneration of the disturbed endometrium. The presence of engrafted Rhodamine B labelled mitochondria was quantified at 12, 24, 48, and 72 h after transplantation.
RESULTS: Detection of human-specific mitochondria mRNA in recipient rat uterus showed significant up-regulation of MT ATP-8, MT COX-1, MT COX -3, MT COX -2, MT ATP-6 (p = 0.009) in the hMTx treated group compared to the disturbed endometrium group. The hMTx group demonstrated showed regeneration through increased expressions of α-SMA, CK-18, CK-19, Connexin-40, E Cadherin, Claudin-1, Zona Occludin as compared with disturbed endometrium group. Experimental hMTx endometrial cells had significantly higher values of activities of NADH, NADPH, Cytochrome B5, Cytochrome P450, Complex I, Complex II, Complex III, Complex IV compared with disturbed endometrium indicating the regeneration of damaged endometrial cells at 72 h.
CONCLUSIONS: Intrauterine hMTx was accounted to improve endometrial junction protein thus regeneration in the disturbed endometrium. Our Data provide the first evidence that hMTx promotes endometrial regeneration in the disturbed endometrium, paving the way for the development of a novel approach to human endometrial regeneration.

Keywords:  Endometrial regeneration; Human placenta derived Mitochondria; Mitochondrial Transplantation; Platelet Rich Plasma

DOI:  https://doi.org/10.1007/s12015-023-10516-2
EMBO Rep. 2023 Feb 27. e54731

Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.

Linbo Chen, Qianping Zhang, Yuanyuan Meng, Tian Zhao, Chenglong Mu, Changying Fu, Caijuan Deng, Jianyu Feng, Siling Du, Wei Liu, Guangfeng Geng, Kaili Ma, Hongcheng Cheng, Qiangqiang Liu, Qian Luo, Jiaojiao Zhang, Zhanqiang Du, Lin Cao, Hui Wang, Yong Liu, Jianping Lin, Guo Chen, Lei Liu, Sin Man Lam, Guanghou Shui, Yushan Zhu, Quan Chen.

  Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA-induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose-, palmitate-, and cholesterol-enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non-alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality.

Keywords:  FUNDC1; fatty acid metabolism; membrane protein dimerization; mitochondrial quality control

DOI:  https://doi.org/10.15252/embr.202254731